Preparation of 6-methyl steroids of the pregnane series



United States Patent Serial No. 686,564 1cm. cuz'spz'aasn No Drawing.

This invention relates to 6 from "the cyclo eriran f more"specificallyfto 6mm'thyl-fia liydrbxy A p g aim-atone, 6=rnethyl-lbujl7=oxidbJieprbgheue-Sp-bl-ZW one and esters,

nd ewmethyl 1Gaji7a-bxido fl4pregnene- 3,2lJ-dioue. "6' methylfsubstitu'ents la're known "to increase certain specific physiologicalactivities. high "progestional activity is exhibited by the6a-me'thyl-17u-hydroxy progesterone as disclosed in the copefidi'ngapplication S. N. "686,563 filed simultaneously herewith by Bja teLoken. Even more advantageous, "the 6a-m'ethyl-l7a acetoxy progesteronehas d'ral pitfgestional activity. Furthermore, the novel compoundscomprising this invention can also be used as intermediates in themanufacture of other fi-methylated steroids, in the manner described inthe aforementioned copending application.

In general terms the synthesis of these compounds is effected asfollows: 6-methyl-A -pregnadiene-3;8-ol-20- one acetate, prepared asdescribed inthe Miramontes et al. copending patent application S. N.686,562 filed simultaneously herewith is treated with alkaline hydrogenperoxide in an organic solvent like methanol or methanol-chloroformmixture and the solution allowed to stand at room temperature forseveral hours. The reaction is then worked up by diluting with water andextracting the precipitate formed with chloroform. The chloroformsolution is washed with water, dried over sodium sulfate and evaporatedalmost to dryness. The residue is treated with ether whereupon acrystalline precipitate of 6-methyl- 16a,17a-oxido-A -pregnene-3B-ol isformed. In order to obtain 6a-methyl-16a,17a-oxido-A -pregnene 3,20dione the above mentioned epoxy-pregnadienol is subjected to Oppenaueroxidation whereby the 3fl-hydroxyl is converted to the 3-ketone andthedouble bond is brought to conjugation. This compound is thentransformed into a brcmohydrin by reacting it with hydrobromic acid inacetic acid; the bromohydrin is isolated by precipitation with water andfiltration or else it may be extracted with ether. This bromohydrin isconverted to the desired 16mmethyl-17a-hydroxy-A -pregnene-3,ZO-dione bysplitting off the bromine atom at C by means of Raney nickel catalystused in refluxing methanol.

The synthesis may be represented by the following formulae:

CH (EH; do 0 o l CHQC 0 0 H0 H: H: I I! 2,878,247 Patented Mar. 17.,1959 EXAMPLE I 6-methyl-1 6 a,1 7e-oxido-A -pregnene-3p-0l-2O-one Asolution of 5 g. of 6-methy1-A -pregnadiene-35-ol- 20-one acetate (1) in300 cc. of methanol is treated at room temperature with 1.8 g. of sodiumhydroxide dissolved in 10 cc. of water and with 18 cc. of 35% hydrogenperoxide. This mixture is then kept at room temperature for 24 hoursafter which it is poured into water and the solid precipitate formedextracted three times with chloroform. The chloroform solution is washedwith water, dried over anhydrous sodium sulfate and evaporated almost todryness. The residue crystallizes in thin colorless plates when someether is added to it. The crystalline solid is collected by filtration,4 g., M. P. 172- 175 C.; crystallization from acetone-ether raised theM. P. to 178-181 C. (analytical sample, M. P. 180-183 C., recrystallizedfrom the same solvent); [(11 -4.17 (chlf.). Analysis.Calcd. for022113203: C, 76.70; H, 9.36. Found: C, 76.87; H, 9.45.

EXAMPLE II Reacting the 6-methyl derivative (1) in the same man nerdescribed in Example I, but using a chloroformmethanol mixture in placeof methanol alone yielded the same 16a,17a-epoxide showing identicalconstants as those mentioned in Example 1.

EXAMPLE III 6a-methyl-1 6 a,] 7a-oxida-A -pregnen e-3,20-dione Asolution of 5 g. of epoxide (II) in 10f) cc. of toluene is distilleduntil 25 cc. of solvent are removed. To this solution is added 50 cc. ofcyclohexanone and a solution of 10 g. of aluminum iso-propoxide in 100cc. of toluene. The mixture is refluxed for one half hour and when coolit is poured into ice-water acidified with dilute sulfuric acid, andthen extracted with benzene twice. The combined extracts aresteam-distilled to eliminate the cyclohexanone, and the residue isextracted with ether. The ether solution, after washing with water twiceand drying over anhydrous sodium sulfate, is evaporated to dry ness andthe residue is chromatographed over alumina;

elutions'with hexane-benzene 50:50 afiord a crystalline solid M. P.146-158" C.;

EIOE mu EXAMPLE 1v fia-methyl-M-pregnene-I7a-ol-3,20-dione (6oz-methylI7u-hydroxy progesterone) The epoxide III described in Example III (500mg.) is reacted with excess hydrobromic acid in acetic acid solution atroom temperature for one half hour. The mixture is poured into ice-waterand the bromohydrin is either collected by filtration (M. P. 95-100 C.)or extracted with ether. The dry bromohydrin is refluxed two hours inmethanol solution with twice its weight of Raney nickel. The Raneynickel is removed by filtration, and the methanol solution is evaporatedalmost to dryness. The residue crystallizes overnight in colorlessneedles (350 mg.), M. P. 205208 C. Recrystallization from aqueousacetone affords a product, M. P.'2l1213 C.; [M +78 (chlf.);

EtOH max ' hydrobromic acid is eflected in What is claimed is: 1.6-me'thyl-16:1,17e-oxido-A -pregnene-3 8-ol-2O-one.

2. 6a-methyl-16a,17a-oxido-A -pregnene-3,20-dione.

3. 6a-methyl 16B bromo A pregnene-17a-ol-3,20- dione. 1

4. The process for converting G-methyl E -pregnadiene-3p-ol-20-oneacetate to 6a-methyl-17a hydroxy progesteronewhich comprises contactingthe pregnadiene with hydrogen peroxide whereby the 16,17 position isepoxidized and the 3-acetoxy group is hydrolyzed; thereafter contactingthe resulting 16a,17u-oxido-A -pregnene- 3/3-ol-20-one with aluminumisopropoxide whereby the pregnene is converted to 16a,17a-oxido-A-pregnene-3,20

dionef then contacting the resulting dione with hydrobromic acid wherebythe dione is converted to the bromohydrin; and finally contacting thebromohydrin with a hydrogenating agent to form the desired 6a-methyl-17ahydroxy progesterone.

5. The process of claim 4 wherein the epoxidation is efiected in analkaline solution of hydrogen peroxide in a solvent selected from thegroup consisting of methanol and mixtures of methanol with chloroform.

6. The process. of claim 4 wherein the treatment with a solution ofhydrobromic acid in acetic acid.

7. The process of claim 4 wherein the hydrogenation is effected byreflux of the steroid in methanol in the presence of Raney nickel.

No references cited.

1. 6-METHYL-1LA, 17A-OXIDO-$5-PREGNENE-3B-OL-20-ONE 2.LA-METHYL-1LA,17A-OXIDO-$4PREGNENE-3,20-DIONE.
 3. 6A-METHYL - 16B -BROMO-$4 - PREGNENE-1MA-OL-3,20DIONE.